The present invention relates to antibiotic compounds an n particular to antibiotic compounds containing an oxazolidinone ring. This invention further relates to processes for their preparation, to intermediates useful in their preparation, to their use as therapeutic agents and to pharmaceutical compositions containing them.
The international microbiological community continues to express serious concern that the evolution of antibiotic resistance could result in strains against which currently available antibacterial agents will be ineffective. In general, bacterial pathogens may be classified as either Gram-positive or Gram-negative pathogens. Antibiotic compounds with effective activity against both Gram-positive and Gram-negative pathogens are generally regarded as having a broad spectrum of activity. The compounds of the present invention are regarded primarily as effective against Gram-positive pathogens because of their particularly good activity against such pathogens.
Gram-positive pathogens, for example Staphylococci, Enterococci, Streptococci and mycobacteria, are particularly important because of the development of resistant strains which are both difficult to treat and difficult to eradicate from the hospital environment once established. Examples of such strains are methicillin resistant staphylococcus (MRSA), methicillin resistant coagulase negative staphylococci (MRCNS), penicillin resistant streptococcus pneumoniae and multiply resistant Enterococcus faecium. 
The major clinically effective antibiotic for treatment of such resistant Gram-positive pathogens is vancomycin. Vancomycin is a glycopeptide and is associated with nephrotoxicity and ototoxicity. Furthermore, and most importantly, antibacterial resistance to vancomycin and other glycopeptides is also appearing. This resistance is increasing at a steady rate rendering these agents less and less effective in the treatment of Gram-positive pathogens.
The present inventors have discovered a class of antibiotic compounds containing an oxazolidinone ring which has useful activity against Gram-positive pathogens including MRSA and MRCNS and, in particular, against various strains exhibiting resistance to vancomycin and against E. faecium strains resistant to both aminoglycosides and clinically used xcex2-lactams.
We have now discovered a narrow range of compounds that is not suggested by the art and which has good activity against a broad range of Gram-positive pathogens including organisms known to be resistant to most commonly used antibiotics. In comparison with compounds described in the art (for example Walter A. Gregory et al in J. Med.Chem. 1990, 33, 2569-2578 and Chung-Ho Park et al in J.Med.Chem. 1992, 35, 1156-1165) the compounds also possess a favourable toxicological profile.
Accordingly the present invention provides a compound of the formula (I): 
wherein:
R1 is hydroxy, chloro, fluoro, (1-4C)alkanesulfonyloxy, amino, azido, (1-4C)alkoxy, (1-4C)alkylthio, (1-4C)alkylaminocarbonyloxy; or of the formula xe2x80x94NHC(xe2x95x90O)Rb wherein Rb is hydrogen, (1-4C)alkoxy, amino, chloromethyl, dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl, methylamino, dimethylamino or (1-4C)alkyl;
or R1 is of the formula xe2x80x94NHS(O)n(1-4C)alkyl wherein n is 0, 1 or 2;
R2 and R3 are independently hydrogen or fluoro;
D is O, S, SO, SO2 or NR7;
when D is O, R4 and R5 are independently hydroxy, bromo, oxo (xe2x95x90O), (1-4C)alkyl,
(1-4C)alkanoylamino-(1-4C)alkyl, hydroxy-(1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, AR-oxymethyl, AR-thiomethyl (wherein AR is as defined hereinbelow) or independently as defined for R7 hereinbelow;
when D is S, SO, SO2 or NR7, R4 and R5 are independently oxo (xe2x95x90O), (1-4C)alkyl, (1-4C)alkanoylamino-(1-4C)alkyl, hydroxy-(1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, AR-oxymethyl, AR-thiomethyl (wherein AR is as defined hereinbelow) or independently as defined for R7 hereinbelow;
R6 is hydrogen, (1-4C)alkyl, hydroxy, (1-4C)alkoxy or (2-4C)alkanoyloxy;  greater than Axe2x80x94Bxe2x80x94 is of the formula  greater than Cxe2x95x90C(Ra)xe2x80x94,  greater than CHCHRaxe2x80x94or  greater than C(OH)CHRaxe2x80x94( greater than represents two single bonds) wherein Ra is hydrogen or (1-4C)alkyl;
R7 is hydrogen, cyano, 2-((1-4C)alkoxycarbonyl)ethenyl, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl, 2-((1-4C)alkylaminocarbonyl)ethenyl, AR (as defined hereinbelow) or a tetrazole ring system (optionally mono-substituted in the 1- or 2-position of the tetrazole ring) wherein the tetrazole ring system is joined to the nitrogen in NR7 by a ring carbon atom;
or R7 is of the formula R10COxe2x80x94, R10SO2xe2x80x94 or R10CSxe2x80x94wherein R10 is AR (as defined hereinbelow), cyclopentyl or cyclohexyl (wherein the last two-mentioned cycloalkyl rings are optionally mono-or disubstituted by substituents independently selected from (1-4C)alkyl (including geminal disubstitution), hydroxy, (1-4C)alkoxy, (1-4C)alkylthio, acetamido, (1-4C)alkanoyl, cyano and trifluoromethyl), (1-4C)alkoxycarbonyl, hydrogen, amino, trifluoromethyl, (1-4C)alkylamino, di((1-AC)alkyl)amino, 2,3-dihydro-5-oxothiazolo-[3,2-A]pyrimidin-6-yl, 2-(2-furyl)ethenyl, 2-(2-thienyl)ethenyl, 2-phenylethenyl (wherein the phenyl substituent is optionally substituted by up to three substituents independently selected from (1-4C)alkoxy, halo and cyano), 3,4-dihydropyran-2-yl, coumal-5-yl, 5-methoxy4-oxopyran-2-yl, N-acetylpyrrolidin-2-yl, 5-oxo-tetrahydrofuran -2-yl, benzopyranone or (1-10C)alkyl [wherein (1-10C)alkyl is optionally substituted by hydroxy, cyano, halo, (1-10C)alkoxy, trifluoromethyl, (1-4C)alkoxy-1-4C)alkoxy, (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy, (1-4C)alkanoyl, (1-4C)alkoxycarbonyl, amino, (1-4C)alkylamino, di((1-4C)alkyl)amino, (1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino, N-(1-4C)alkyl-N-(2-6C)alkanoylamino, (1-4C)alkylS(O)pNHxe2x80x94, (1-4C)alkylS(O)p((1-4C)alkyl)Nxe2x80x94, fluoro(1-4C)alkylS(O)pNHxe2x80x94, fluoro(1-4C)alkylS(O)p((1-4C)alkyl)Nxe2x80x94, phosphono, (1-4C)alkoxy(hydroxy)phosphoryl, di-(1-4C)alkoxyphosphoryl, (1-4C)alkylS(O)qxe2x80x94, phenylS(O)qxe2x80x94(wherein the phenyl group is optionally substituted by up to three substituents independently selected from (1-4C)alkoxy, halo and cyano), or CY (as defined hereinbelow), wherein p is 1 or 2 and q is 0.1 or 2];
or R10 is of the formula R11C(O)O(1-6C)alkyl wherein R11 is an optionally substituted 5-or 6-membered heteroaryl, optionally substituted phenyl, (1-4C)alkylamino, benzyloxy-(1-4C)alkyl or optionally substituted (1-10C)alkyl;
or R10 is of the formula R12Oxe2x80x94 wherein R12 is optionally substituted (1-6C)alkyl; or R7 is of the formula RdOC(Re)xe2x95x90CH(Cxe2x95x90O)xe2x80x94, RgNxe2x95x90C(Rh)C(xe2x95x90O)xe2x80x94 or RiNHC(Rj)xe2x95x90CHC(xe2x95x90O)xe2x80x94 wherein Rd is (1-6C)alkyl, Re is hydrogen or (1-6C)alkyl, or Rd and Re together form a (3-4C)alkylene chain, Rf is hydrogen, (1-6C)alkyl, hydroxy(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, amino, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy, hydroxy(2-6C)alkoxy, (1-4C)alkylamino(2-6C)alkoxy, di-(1-C)alkylamino(2-6C)alkoxy, Rg is (1-6C)alkyl, hydroxy or (1-6C)alkoxy, Rh is hydrogen or (1-6C)alkyl, Ri is hydrogen, (1-6C)alkyl, optionally substituted phenyl or an optionally substituted 5-or 6-membered heteroaryl and Rj is hydrogen or (1-6C)alkyl;
or R7 is of the formula R14CH(R13) (CH2)m xe2x80x94 wherein m is 0 or 1, R13 is fluoro, cyano, (1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkoxycarbonyl or hydroxy, (provided that when m is 0, R13 is not fluoro or hydroxy) and R14 is hydrogen or (1-4C)alkyl;
wherein AR is optionally substituted phenyl, optionally substituted phenyl(1-4C)alkyl, optionally substituted 5-or 6-membered heteroaryl, optionally substituted naphthyl or an optionally substituted 5/6 or 6/6 bicyclic heteroaryl ring system, in which the bicyclic heteroaryl ring systems may be linked via an atom in either of the rings comprising the bicyclic system, and wherein the mono-and bicyclic heteroaryl ring systems are linked via a ring carbon atom;
wherein CY is a 4,5-or 6-membered cycloalkyl ring, a 5-or 6-membered cycloalkenyl ring, naphthoxy, thiophen-2-yl, indol-1-yl, indol-3-yl, pyrimidin-2-ylthio, 1,4-benzodioxan-6-yl, sulfolan-3-yl, pyridin-2-yl; wherein any of the afore-mentioned ring systems in CY may be optionally substituted by up to three substituents independently selected from halo, (1-4C)alkyl (including geminal disubstitution when CY is a cycloalkyl or cycloalkenyl ring), acyl, oxo and nitro-(1-4C)alkyl; and pharmaceutically-acceptable salts thereof; except that N-((5S)-3-(4-(2-oxo-5,6-dihydropyran)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide is excluded.
In this specification a xe2x80x985-or 6membered heteroarylxe2x80x99 and xe2x80x98heteroaryl (monocyclic) ringxe2x80x99 means a 5-or 6-membered aryl ring wherein 1, 2 or 3 of the ring atoms are selected from nitrogen, oxygen and sulfur. Particular examples of 5-or 6-membered heteroaryl ring systems are furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole and thiophene.
In this specification a xe2x80x985/6 or 6/6 bicyclic heteroaryl ring systemxe2x80x99 and xe2x80x98heteroaryl (bicyclic) ringxe2x80x99 means an aromatic bicyclic ring system comprising a 6-membered ring fused to either a 5 membered ring or another 6 membered ring, the bicyclic ring system containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. Particular examples of 5/6 and 6/6 bicyclic ring systems are indole, benzofuran, benzoimidazole, benzothiophene, benzisothiazole, benzoxazole, benzisoxazole, pyridoimidazole, pyrimidoimidazole, quinoline, quinoxaline, quinazoline, phthalazine, cinnoline and naphthyridine.
In this specification a xe2x80x984-, 5-or 6-membered cycloalkyl ringxe2x80x99 means a cyclobutyl, cyclopentyl or cyclohexyl ring; and a xe2x80x985-or 6-membered cycloalkenyl ringxe2x80x99 a means cyclpentenyl or cyclohexenyl ring.
In this specification the term xe2x80x98alkylxe2x80x99 includes straight chained and branched structures. For example, (1-6C)alkyl includes propyl, isopropyl and tert-butyl. However, references to individual alkyl groups such as xe2x80x9cpropylxe2x80x9d are specific for the straight chained version only, and references to individual branched chain alkyl groups such as xe2x80x9cisopropylxe2x80x9d are specific for the branched chain version only. A similar convention applies to other radicals, for example halo(1-4C)alkyl includes 1-bromoethyl and 2-bromoethyl.
Particular optional substituents for alkyl, phenyl (and phenyl containing moieties) and naphthyl groups and ring carbon atoms in heteroaryl (mono or bicyclic) rings in R11, R12, Ri and AR include halo, (1-4C)alkyl , hydroxy, nitro, carbamoyl, (1-4C)alkylcarbamoyl, di-((1-4C)alkyl)carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, amino, (1-4C)alkylamino, di((1-4C)alkyl)amino, (1-4C)alkyl S(O)qxe2x80x94, (wherein q is 0, 1 or 2), carboxy, (1-4C)alkoxycarbonyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkanoyl, (1-C)alkoxy, (1-4C)alkanoylamino, benzoylamino, benzoyl, phenyl (optionally substituted by up to three substituents selected from halo, (1-4C)alkoxy or cyano), furan, pyrrole. pyrazole. imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, thiophene, hydroxyimino(1-4C)alkyl, (1-4C)alkoxyimino(1-4C)alkyl, hydroxy-(1-4C)alkyl, halo-(1-4C)alkyl, nitro(1-4C)alkyl, amino(1-4C)alkyl, cyano(1-4C)alkyl, (1-4C)alkanesulfonamido, aminosulfonyl, (1-4C)alkylaminosulfonyl and di-((1-4C)alkyl)aminosulfonyl. The phenyl and naphthyl groups and heteroaryl (mono-or bicyclic) rings in R11, Ri and AR may be mono- or disubstituted on ring carbon atoms with substituents independently selected from the above list of particular optional substituents.
Particular optional substituents for ring nitrogen atoms when R7 is tetrazole, in heteroaryl groups in R11, R12, Ri and AR, and in the nitrogen-containing rings in CY, which can be substituted without becoming quaternised include (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl and (1-4C)alkanoyl.
Examples of halo groups include fluoro, chloro and bromo; examples of (1-4C)alkyl, include methyl, ethyl, and propyl and isopropyl; examples of(1-6C)alkyl include methyl, ethyl, propyl, isopropyl, pentyl and hexyl; examples of (1-10C)alkyl include methyl, ethyl, propyl, isopropyl, pentyl, hexyl, heptyl, octyl and nonyl; examples of (1-4C)alkylamino include methylamino, ethylamino and propylamino; examples of di-((1-4C)alkyl)amino include dimethylamino, N-ethyl-N-methylamino, diethylamino, N-methyl-N-propylamino and dipropylamino; examples of (1-4C)alkylS(O)qxe2x80x94 wherein q is 0, 1 or 2 include methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl and ethylsulfonyl; examples of (1-4C)alkanesulfonyloxy include methylsulfonyloxy, ethylsulfonyloxy and propylsulfonyloxy; examples of (1-4C)alkylthio include methylthio and ethylthio; examples of (1-4C)alkylsulfonyl include methylsulfonyl and ethylsulfonyl; examples of (1-4C)alkylaminocarbonyloxy include methylaminocarbonyloxy and ethylaminocarbonyloxy; examples of (1-4C)alkanoylamino(1-4C)alkyl include formamidomethyl, acetamidomethyl and acetamidoethyl; examples of (1-6C)alkoxy-(1-6C)alkyl include methoxymethyl, ethoxymethyl and 2-methoxyethyl; examples of (1-4C)alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; examples of (2-4C)alkanoyloxy include acetyloxy and propionyloxy; examples of (1-4C)alkoxy include methoxy, ethoxy and propoxy; examples of (1-6C)alkoxy include methoxy, ethoxy, propoxy and pentoxy; examples of hydroxy-(2-6C)alkoxy include 2-hydroxyethoxy and 3-hydroxypropoxy; examples of (1-4C)alkylamino-(2-6C)alkoxy include 2-methylaminoethoxy and 2-ethylaminoethoxy; examples of di-(1-4C)alkylamino-(2-6C)alkoxy include 2-dimethylaminoethoxy and 2-diethylaminoethoxy; examples of (1-4C)alkoxy-(1-4C)alkoxy and (1-6C)alkoxy(1-6C)alkoxy include methoxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy and 3-methoxypropoxy; examples of (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy include 2-(methoxymethoxy)ethoxy, 2-(2-methoxyethoxy)ethoxy; 3-(2-methoxyethoxy)propoxy and 2-(2-ethoxyethoxy)ethoxy; examples of (1-4C)alkanoylamino and (1-6C)alkanoylamino include formamido, acetamido and propionylamino; examples of (1-4C)alkoxycarbonylamino include methoxycarbonylamino and ethoxycarbonylamino; examples of N-(1-4C)alkyl-N2-6C)alkanoylamino include N-methylacetamido, N-ethylacetamido and N-methylpropionamido; examples of (1-4C)alkylS(O)pNHxe2x80x94 wherein p is 1 or 2 include methylsulfinylamino, methylsulfonylamino, ethylsulfinylamino and ethylsulfonylamino; examples of (1-4C)alkylS(O)p((1-4C)alkyl)NHxe2x80x94 wherein p is 1 or 2 include methylsulfinylmethylamino, methylsulfonylmethylamino, 2-(ethylsulfinyl)ethylamino and 2-(ethylsulfonyl)ethylamino; examples of fluoro(1-4C)alkylS(O)pNHxe2x80x94wherein p is 1 or 2 include trifluoromethylsulfinylamino and trifluoromethylsulfonylamino; examples of fluoro(1-4C)alkylS(O)p((1-4C)alkyl)NHxe2x80x94 wherein p is I or 2 include trifluoromethylsulfinylmethylamino and trifluoromethylsulfonylmethylamino examples of (1-4C)alkoxy(hydroxy)phosphoryl include methoxy(hydroxy)phosphoryl and ethoxy(hydroxy)phosphoryl; examples of di-(1-4C)alkoxyphosphoryl include di-methoxyphosphoryl, di-ethoxyphosphoryl and ethoxy(methoxy)phosphoryl; examples of 2(1-4C)alkoxycarbonyl)ethenyl include 2-(methoxycarbonyl)ethenyl and 2-(ethoxycarbonyl)ethenyl; examples of 2-cyano-2-((1-4C)alkyl)ethenyl include 2cyano-2-methylethenyl and 2-cyano-2-ethylethenyl; examples of 2-4(1-4C)alkylaminocarbonyl)ethenyl include 2-(methylaminocarbonyl)ethenyl and 2ethylaminocarbonyl)ethenyl; examples of benzyloxy(1-4C)alkyl include benzyloxymethyl and benzyloxyethyl; examples of phenyl(1-4C)alkyl include benzyl and phenethyl; examples of phenylS(O)q wherein q is 0, 1 or 2 are phenylthio, phenylsulfinyl and phenylsulfonyl respectively; examples of (1-4C)alkylcarbamoyl include methylcarbamoyl and ethylcarbamoyl; examples of di((1-4C)alkyl)carbamoyl include di(methyl)carbamoyl and di(ethyl)carbamoyl; examples of a (3-4C)alkylene chain are trimethylene or tetramethylene; examples of (2-4C)alkenyl include alkyl and vinyl; example; (2-4C)alkynyl include ethynyl and 2-propynyl; examples of (1-4C)alkanoyl include formyl, acetyl and propionyl; examples of hydroxyimino(1-4C)alkyl include hydroxyiminomethyl, 2-(hydroxyimino)ethyl and 1-(hydroxyimino)ethyl; examples of(1-4C)alkoxyimino-(1-4C)alkyl include methoxyiminomethyl, ethoxyiminomethyl, 1-(methoxyimino)ethyl and 2-(methoxyimino)ethyl; examples of hydroxy(1-4C)alkyl and hydroxy(1-6C)alkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl; examples of halo(1-4C)alkyl include, halomethyl, 1-haloethyl, 2-haloethyl, and 3-halopropyl; examples of nitro(1-4C)alkyl include nitromethyl, 1-nitroethyl, 2-nitroethyl and 3-nitropropyl; examples of amino(1-4C)alkyl include aminomethyl, 1-aminoethyl, 2-aminoethyl and 3-aminopropyl; examples of cyano(1-4C)alkyl include cyanomethyl, 1-cyanoethyl, 2-cyanoethyl and 3-cyanopropyl; examples of(1-4C)alkanesulfonamido include methanesulfonamido and ethanesulfonamido; examples of (1-4C)alkylaminosulfonyl include methylaminosulfonyl and ethylaminosulfonyl; and examples of di-(1-4C)alkylaminosulfonyl include dimethylaminosulfonyl, diethylaminosulfonyl and N-methyl-N-ethylaminosulfonyl.
Suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulfonate, fumarate, hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulfuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine or amino acids for example lysine. There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions. A preferred pharmaceutically-acceptable salt is the sodium salt.
However, to facilitate isolation of the salt during preparation, salts which are less soluble in the chosen solvent may be preferred whether pharmaceutically-acceptable or not.
The compounds of the formula (1) may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the formula (I). Examples of pro-drugs include in-vivo hydrolysable esters of a compound of the formula (I).
An in-vivo hydrolysable ester of a compound of the formula (I) containing carboxy or hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically-acceptable esters for carboxy include (1-6C)alkoxymethyl esters for example methoxymethyl, (1-6C)alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, (3-8C)cycloalkoxycarbonyloxy(1-6C)alkyl esters for example 1-cyclohexylcarbonyloxyethyl, 1,3-dioxolen-2-onylmethyl esters for example 5-methyl-1,3-dioxolen-2-onylmethyl; and (1-6C)alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.
An in-vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and xcex1-acyloxyalkyl ethers and related compounds which as a result of the in-vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of xcex1-acyloxyalkyl ethers include acetoxymethoxy and 2.2-dimethylpropionyloxymethoxy. A selection of in-vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
The compounds of the present invention have a chiral centre at the C-5 position of the oxazolidinone ring. The pharmaceutically active enantiomer is of the formula: 
The present invention includes the pure enantiomer depicted above or mixtures of the 5R and 5S enantiomers, for example a racemic mixture. If a mixture of enantiomers is used, a larger amount (depending upon the ratio of the enantiomers) will be required to achieve the same effect as the same weight of the pharmaceutically active enantiomer. For the avoidance of doubt the enantiomer depicted above could be either 5R or 5S depending upon the value of R1. For example, when R1 is acetamido, the enantiomer depicted above is the 5S enantiomer and when R1 is hydroxy, the enantiomer depicted above is the 5R enantiomer.
Furthermore. some compounds of the formula (I) may have other chiral centres, and some compounds of the formula (I) may exist as one or more regioisomers. It is to be understood that the invention encompasses all such optical, diastereo-and regio-isomers that possess antibacterial activity.
The invention relates to all tautomeric forms of the compounds of the formula (I) that possess antibacterial activity.
It is also to be understood that certain compounds of the formula (1) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess antibacterial activity.
In a preferred aspect of the invention there is provided a compound of the formula (I) as defined above, except that in the definition of R4 and R5, neither R4 nor R5 can be oxo (xe2x95x90O).
In another aspect the present invention provides a compound of the formula (I)
wherein:
R1 is hydroxy, chloro, fluoro, (1-4C)alkanesulfonyloxy, amino, azido, (1-4C)alkoxy, (1-4C)alkylthio, (1-4C)alkylaminocarbonyloxy, or of the formula xe2x80x94NHC(xe2x95x90O)Rb wherein Rb is hydrogen. (1-4C)alkoxy, amino, chloromethyl, dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl, methylamino, dimethylamino or (1-4C)alkyl;
or R1 is of the formula xe2x80x94NHS(O)n(1-4C)alkyl wherein n is 0, 1 or 2;
R2 and R3 are independently hydrogen or fluoro;
when D is O, R4 and R5 are independently hydrogen, hydroxy, bromo, oxo (xe2x95x90O), (1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl or independently as defined for R7 hereinbelow;
when D is S, SO, SO2 or NR7, R4 and R5 are independently hydrogen, oxo (xe2x95x90O), (1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl or independently as defined for R7 hereinbelow;
R6 is hydrogen, (1-4C)alkyl, hydroxy, (1-4C)alkoxy or (2-4C)alkanoyloxy;
 greater than Axe2x80x94Bxe2x80x94 is of the formula  greater than Cxe2x95x90C(Ra),  greater than CHCHRa or  greater than C(OH)CHRaxe2x80x94( greater than represents two single bonds) wherein Ra is hydrogen or (1-4C)alkyl;
D is O,S, SO, SO2or NR7;
wherein R7 is hydrogen, cyano, 2-((1-4C)alkoxycarbonyl)ethenyl, 2-((1-4C)alkylaminocarbonyl)ethenyl, optionally substituted phenyl, optionally substituted phenyl(1-4C)alkyl, optionally substituted 5-or 6-membered heteroaryl, optionally substituted naphthyl or optionally substituted 5/6 or 6/6 bicyclic heteroaryl ring system wherein the heteroaryl ring systems are joined to the the nitrogen by a ring carbon atom;
or R7 is of the formula R10 COxe2x80x94or R10SO2xe2x80x94wherein R10 is (1-4C)alkoxycarbonyl, amino, (1-4C)alkylamino, di((1-4C)alkyl)amino or (1-6C)alkyl [wherein (1-6C)alkyl is optionally substituted by hydroxy, cyano, amino, (1-4C)alkoxy, (1-4C)alkanoyl, (1-4C)alkylamino, di((1-4C)alkyl)amino, (2-6C)alkanoylamino, N-(1-4C)alkyl-N-(2-6C)alkanoylamino, (1-4C)alkylS(O)pNHxe2x80x94, (1-4C)alkylS(O)p((1-4C)alkyl)Nxe2x80x94, phosphono, (1-4C)alkoxy(hydroxy)phoryl, di-(1-4C)alkoxyphosphoryl or (1-4C)alkylS(O)q wherein p is 1 or 2 and q is 0, 1 or 2];
or R10 is of the formula R11 C(O)O(1-6C)alkyl wherein R11 is optionally substituted 5-or 6-membered heteroaryl, optionally substituted phenyl or optionally substituted (1-6C)alkyl;
or R10 is of the formula R12 Oxe2x80x94 wherein R12 is optionally substituted (1-6C)alkyl; or R7 is of the formula RdOC(Re)xe2x95x90CH(Cxe2x95x90O)xe2x80x94, RfC(xe2x95x90O)C(xe2x95x90O)xe2x80x94, RgNxe2x95x90C(Rh)C(xe2x95x90O)xe2x80x94 or RiNHC(Rj)xe2x95x90CHC(xe2x95x90O)xe2x80x94 wherein Rd is (1-6C)alkyl, Re is hydrogen or (1-6C)alkyl or Rd and Re together form a (3-4C)alkylene chain, Rf is hydrogen, (1-6C)alkyl, hydroxy(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, amino, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy, hydroxy(2-6C)alkoxy, (1-4C)alkylamino(2-6C)alkoxy, di(1-4C)alkylamino(2-6C)alkoxy, Rg is (1-6C)alkyl, hydroxy or (1-6C)alkyl, Rh is hydrogen or (1-6C)alkyl, Ri is (1-6C)alkyl, phenyl or a 5-or 6-membered heteroaryl and Rj is hydrogen or (1-6C)alkyl;
or R7 is of the formula R14CH(R13) (CH2)mxe2x80x94 wherein m is 0 or 1, R13 is fluoro, cyano, (1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkoxycarbonyl or hydroxy; (provided that when m is 0, R13 is not fluoro or hydroxy) and R14 is hydrogen or (1-4C)alkyl;
and pharmaceutically-acceptable salts thereof; except that N-((5S)-3-(4-(2-oxo-5,6-dihydropyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide; N-((5S)-3-(3-ethyl-4-(2-oxo-5,6dihydrothiapyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide and N-((5S)-3-(3-hydroxy-4-(2-oxo-1,2,5,6-tetrahydropyrid-4-yl)phenyl) -2-oxooxazolidin-5-ylmethyl)acetamide are excluded.
In a preferred aspect of the invention there is provided a compound of the formula (I) as defined above in the section relating to another aspect of the present invention, except that Ra is hydrogen (rather than hydrogen or (1-4C)alkyl).
In another preferred aspect of the invention there is provided a compound of the formula (I) as defined above in the section relating to another aspect of the present invention, except that in the definition of R4 and R5, neither R4 nor R5 can be oxo (xe2x95x90O).
In a further aspect the present invention provides a compound of the formula (I) wherein:
R1 is of the formula xe2x80x94NHC(xe2x95x90O)(1-4C)alkyl or xe2x80x94NHS(O)n(1-4C)alkyl wherein n is 0, 1 or 2;
R2and R3 are independently hydrogen or fluoro;
R4 and R5 are independently hydrogen, or methyl;
 greater than Axe2x80x94Bxe2x80x94 is of the formula  greater than Cxe2x95x90CH,  greater than CHCH2 or  greater than C(OH)CH2xe2x80x94 ( greater than represents two single bonds) wherein Ra is hydrogen or (1-4C)alkyl;
D is O, S, SO, SO2 or NR7;
wherein R7 is hydrogen, optionally substituted phenyl, optionally substituted phenyl(1-4C)alkyl, optionally substituted 5- or 6-membered heteroaryl, optionally substituted naphthyl or optionally substituted 5/6 or 6/6 bicyclic heteroaryl ring system wherein the heteroaryl ring systems are joined to the the nitrogen in NR7 by a ring carbon atom;
or R7 is of the formula R10COxe2x80x94 or R10SO2xe2x80x94wherein R10 is amino, (1-4C)alkylamino, di((1-4C)alkyl)amino or (1-6C)alkyl [wherein (1-6C)alkyl is optionally substituted by hydroxy, cyano, amino, or (1-4C)alkylS(O)q wherein q is 1 or 2];
or R10 is of the formula R11C(O)O(1-6C)alkyl wherein R11 is optionally substituted 5- or 6-membered heteroaryl, optionally substituted phenyl or optionally substituted (1-6C)alkyl;
or R10 is of the formula R12Oxe2x80x94 wherein R12 is optionally substituted (1-6C)alkyl;
or R7 is of the formula R14CH(R13)(CH2)mxe2x80x94 wherein m is 0 or 1, R13 is fluoro, cyano, (1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkoxycarbonyl or hydroxy; (provided that when m is 0, R13 is not fluoro or hydroxy) and R14 is hydrogen or (1-4C)alkyl;
and pharmaceutically-acceptable salts thereof.
In the sections above relating to another aspect of the present invention, and to a further aspect of the present invention, xe2x80x985- or 6-membered heteroarylxe2x80x99 means a 5- or 6-membered ring wherein 1, 2 or 3 of the ring atoms are selected from nitrogen, oxygen and sulfur. Particular examples of such 5- or 6-membered heteroaryl ring systems are imidazole. triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole and thiophene.
Also, in the sections above relating to another aspect of the present invention, and to a further aspect of the present invention, a xe2x80x985/6 or 6/6 bicyclic heteroaryl ring systemxe2x80x99 means an aromatic bicyclic ring system comprising a 6-membered ring fused to either a 5 membered ring or another 6 membered ring, the bicyclic ring system containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. Particular examples of 5/6 and 6/6 bicyclic ring systems are benzofuran, benzoimidazole, benzothiophene, benzisothiazole, benzoxazole, benzisoxazole, pyridoimidazole, pyrimidoimidazole, quinoline, quinoxaline, quinazoline, phthalazine, cinnoline and naphthyridine.
Particularly preferred compounds of the invention comprise a compound of the formula (I), or pharmaceutically-acceptable salts thereof, wherein the substituents A, B, D, R1 to R14 and other optional substituents mentioned above have the values disclosed hereinbefore, or any of the following values:
(a) Preferably R1 is hydroxy, chloro, fluoro, methanesulfonyloxy, amino, azido, methoxy, methylthio, methylaminocarbonyloxy, or of the formula xe2x80x94NHC(xe2x95x90O)Ra wherein Ra is hydrogen, methoxy, amino, chloromethyl, dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl, methylamino, dimethyl amino or (1-4C)alkyl or R1 is of the formula xe2x80x94NHS(O)n(1-4C)alkyl wherein n is 0, 1 or 2.
(b) More preferably R1 is hydroxy, chloro, fluoro, methanesulfonyloxy, or of the formula xe2x80x94NHC(xe2x95x90O)Ra wherein Ra is hydrogen, methoxy, amino, chloromethyl dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl or (1-4C)alkyl or R1 is of the formula xe2x80x94NHS(O)n(1-4C)alkyl wherein n is 0,1 or 2.
(c) Yet more preferably R1 is hydroxy, or of the formula xe2x80x94NHC(xe2x95x90O)Ra wherein Ra is (1-4C)alkyl or R1 is of the formula xe2x80x94NHS(O)n(1-4C)alkyl wherein n is 0, 1 or 2.
(d) Yet more preferably R1 is of the formula xe2x80x94NHC(xe2x95x90O)(1-4C)alkyl or xe2x80x94NHS(O)n(1-4C)alkyl.
(e) Yet more preferably R1 is of the formula xe2x80x94NHC(xe2x95x90O)(1-4C)alkyl.
(f) Most preferably R1 is acetamido.
(g) In another aspect R1 is hydroxy.
(h) Preferably, at least one of R2 and R3 is hydrogen.
(i) Preferably R6 is hydrogen or (1-4C)alkyl.
(j) Most preferably one of R2 and R3 is hydrogen and the other is fluoro.
(k) Preferably  greater than Axe2x80x94Bxe2x80x94 is of the formula  greater than Cxe2x95x90CHxe2x80x94 or  greater than CHCH2xe2x80x94.
(l) Most preferably  greater than Axe2x80x94Bxe2x80x94 is of the formula  greater than Cxe2x95x90CHxe2x80x94.
(m) Preferably R4 and R5 are independently hydrogen, (1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, hydroxymethyl, (1-4C)alkoxymethyl or carbamoyl.
(n) More preferably, R4 and R5 are independently hydrogen, AR-oxymethyl or AR-thiomethyl. Especially preferred is AR when it is optionally substituted phenyl, phenyl(1-4C)alkyl, naphthyl, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole oxazole, isothiazole, thiazole or thiophene.
(o) Most preferably R4 or R5 is hydrogen.
(p) Preferably R6 is hydrogen or (1-4C)alkyl.
(q) More preferably R6 is hydrogen or methyl.
(r) Most preferably R6 is hydrogen.
(s) Preferably D is O, S or of the formula NR7.
(t) Preferably D is O.
(u) Preferred substituents for phenyl and carbon atoms in heteroaryl (mono- and bicyclic) ring systems in R7 and R11 include halo, (1-4C)alkyl, hydroxy, nitro, amino, cyano, (1-4C)alkylS(O)pxe2x80x94 and (1-4C)alkoxy.
(v) Preferred optional substituents for (1-6C)alkyl in R11 are hydroxy, cyano, amino, (1-4C)alkylamino, di((1-4C)alkyl)amino, (1-4C)alkylS(O)p(wherein p is 1 or 2), carboxy, (1-4C)alkoxycarbonyl, (1-4C)alkoxy, piperazino or morpholino.
(w) Preferred optional substituents for (1-6C)alkyl in R12 are hydroxy, (1-4C)alkoxy, cyano, amino, (1-4C)alkylamino, di(C1-2alkyl)amino, (1-4C)alkylS(O)pxe2x88x92 (wherein p is 1 or 2).
(x) Preferably the ring systems in AR are unsubstituted.
(y) Preferably the 5/6 or 6/6 bicyclic ring system in R4, R5, R7 or R10 is unsubstituted.
(z) Preferably 5- or 6-membered heteroaryl rings in R4, R5, R7 or R10 or R11 are unsubstituted.
(a1) Preferably 5- or 6-membered heteroaryl in R11 is pyridyl or imidazol-1-yl.
(b1) Preferably R12 is (1-6C)alkyl. Most preferably R12 is tert-butyl or methyl.
(c1) Preferably R13 is cyano or fluoro.
(d1) Preferably R14 is hydrogen.
(e1) Preferably R10 is (1-4C)alkoxycarbonyl, hydroxy(1-4C)alkyl,(1-4C)alkyl. (1-4C)alkylamino, dimethylamino(1-4C)alkyl, (1-4C)alkoxymethyl, (1-4C)alkanoylmethyl, (1-4C)alkanoyloxy(1-4C)alkyl, (1-5C)alkoxy or 2-cyanoethyl.
(f1) More preferably R10 is methoxycarbonyl, hydroxymethyl, methyl, methylamino, dimethylaminomethyl, methoxymethyl, acetoxymethyl, methoxy, methylthio, naphthyl, tert-butoxy or 2-cyanoethyl.
(g1) Preferably R7 is hydrogen, cyano, benzyl, pyrimidyl, imidazolyl, triazolyl or of the formula R10COxe2x80x94 or R10SO2xe2x80x94.
(h1) Preferably R7 is hydrogen, cyano, benzyl, methoxycarbonyl, tert-butoxycarbonyl, hydoxyacetyl, dimethylaminoacetyl, acetyloxymethylcarbonyl, methoxyacetyl, methoxalkyl, methylcarbamoyl or methanesulfonyl.
(
i1) Preferably when R10 is benzopyranone it is 4-oxo-benzopyran-2-yl.
(j1) Preferably CY is naphthoxy, especially naphth-1-oxy or naphth-2-oxy.
Therefore, especially preferred compounds of the present invention are of the formula (IB): 
wherein R1 is hydroxy or acetamido; R2 is hydrogen or fluoro and R4 and R5 are independently hydrogen, hydroxy, bromo, (1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, hydroxymethyl, (1-4C)alkoxymethyl or carbamoyl; and pharmaceutically-acceptable salts thereof.
Of the above especially preferred compounds of the formula (IB), particularly preferred compounds are those wherein R1 is acetamido; R2 is hydrogen or fluoro and R4 and R5 are independently hydrogen, hydroxy, bromo, (1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, hydroxymethyl, (1-4C)alkoxymethyl or carbamoyl; and pharmaceutically-acceptable salts thereof.
Further especially preferred compounds of the invention are of the formula (IB) wherein R1 is acetamido; R2 is hydrogen or fluoro and R4 and R5 are independently hydrogen, AR-oxymethyl or AR-thiomethyl (wherein AR is phenyl, phenyl(1-4C)alkyl, naphthyl, furan, pyrrole, pyrazole. imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole or thiophene); and pharmaceutically-acceptable salts thereof.
Further, especially preferred compounds of the invention are of the formula (IC): 
wherein R1 is hydroxy or acetamido; R2 is hydrogen or fluoro; R4 and R5 are independently hydrogen. AR-oxymethyl or AR-thiomethyl (wherein AR is phenyl, phenyl(1-4C)alkyl, naphthyl, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole or thiophene), hydroxy, bromo, (1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, hydroxymethyl, (1-4C)alkoxymethyl or carbamoyl and R7 is cyano, pyrimidin-2-yl, tetrazol-5-yl, 2-cyanoethenyl, 2-cyano-2-(1-4C)alkyl)ethenyl or R7 is of formula R10COxe2x80x94 or R10SO2xe2x80x94 (wherein R10 is hydrogen, (1-4C)alkyl [optionally substituted by hydroxy, (1-4C)alkoxy, (1-4C)alkylS(O)q, (1-4C)alkylamino, (1-4C)alkanoyl, naphthoxy, (2-6C)alkanoylamino or (1-4C)alkylS(O)pNHxe2x80x94 wherein p is 1 or 2 and q is 0,1 or 2], phenyl, naphthyl, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, thiophene, benzofuran, benzoimidazole, benzothiophene, benzisothiazole, benzoxazole, benzisoxazole, pyridoimidazole, pyrimidoimidazole, quinoline, quinoxaline, quinazoline, phthalazine, cinnoline or naphthyridine, or R10 is of the formula R11C(O)O(1-6C)alkyl wherein R11 is (1-6C)alkyl), or R7 is of the formula RfC(xe2x95x90O)C(xe2x95x90O)xe2x80x94 wherein Rf is (1-6C)alkoxy; and pharmaceutically-acceptable salts thereof.
Of the above especially preferred compounds of the invention of the formula (IC), particularly preferred compounds are those wherein R1 is acetamido; R2 is hydrogen or fluoro; R4 and R5 are independently hydrogen, AR-oxymethyl or AR-thiomethyl [wherein AR is phenyl, phenyl(1-4C)alkyl, naphthyl, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole or thiophene], hydroxymethyl, (1-4C)alkoxymethyl or carbamoyl and R7 is cyano, pyrimidin-2-yl, tetrazol-5-yl, 2-cyanoethenyl, 2-cyano-2-((1-C)alkyl)ethenyl, or R1 is of the formula R10COxe2x80x94 or R10SO2xe2x80x94 (wherein R10 is hydrogen, (1-4C)alkyl [optionally substituted by hydroxy, (1-4C)alkylS(O)q, (1-4C)alkanoyl or naphthoxy wherein q is 0,1 or 2], phenyl, naphthyl. imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, thiophene, benzofuran, benzoimidazole, benzothiophene, benzisothiazole, benzoxazole, benzisoxazole, pyridoimidazole, pyrimidoimidazole, quinoline, quinoxaline, quinazoline, phthalazine, cinnoline or naphthyridine, or R10 is of the formula R11C(O)O(1-6C)alkyl wherein R11 is (1-6C)alkyl), or R7 is of the formula RfC(xe2x95x90O)C(xe2x95x90O)xe2x80x94 wherein Rf is (1-6C)alkoxy; and pharmaceutically-acceptable salts thereof.
Of the above particularly preferred compounds of the invention of the formula (IC), especially preferred compounds are those wherein R1 is acetamido; R2 is hydrogen or fluoro; R4 and R5 are hydrogen and R7 is cyano, pyrimidin-2-yl, tetrazol-5-yl, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl, or R7 is of the formula R10COxe2x80x94 or R10SO2xe2x80x94 (wherein R10 is hydrogen, (1-4C)alkyl [optionally substituted by hydroxy, (1-4C)alkylS(O)q or (1-4C)alkanoyl wherein q is 0, 1 or 2], phenyl, naphthyl, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, thiophene, benzofuran, benzoimidazole, benzothiophene, benzisothiazole, benzoxazole, benzisoxazole, pyridoimidazole, pyrimidoimidazole, quinoline, quinoxaline, quinazoline, phthalazine, cinnoline or naphthyridine, or R10 is of the formula R11C(O)O(1-6C)alkyl wherein R11 is (1-6C)alkyl), or R7 is of the formula RfC(xe2x95x90O)C(xe2x95x90O)xe2x80x94 wherein Rf is (1-6C)alkoxy; and pharmaceutically-acceptable salts thereof.
Of the above particularly preferred compounds of the invention of the formula (IC), further especially preferred compounds are those wherein R1 is acetamido; R2 is hydrogen or fluoro; R4 and R5 are independently hydrogen, AR-oxymethyl or AR-thiomethyl (wherein AR is phenyl, phenyl(1-4C)alkyl, naphthyl, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole or thiophene), hydroxymethyl, (1-4C)alkoxymethyl or carbamoyl and R7 is cyano, pyrimidin-2-yl, tetrazol-5-yl, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl, or R7 is of the formula R10COxe2x80x94 (wherein R10 is hydrogen, (1-4C)alkyl [optionally substituted by hydroxy, (1-4C)alkylS(O)q or (1-4C)alkanoyl wherein q is 0, 1 or 2], phenyl, naphthyl, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, thiophene, benzofuran, benzoimidazole, benzothiophene, benzisothiazole, benzoxazole, benzisoxazole, pyridoimidazole, pyrimidoimidazole, quinoline, quinoxaline, quinazoline, phthalazine, cinnoline or naphthyridine, or R10 is of the formula R11C(O)O(1-6C)alkyl wherein R11 is (1-6C)alkyl), or R7 is of the formula RfC(xe2x95x90O)C(xe2x95x90O)xe2x80x94 wherein Rf is (1-6C)alkoxy; and pharmaceutically-acceptable salts thereof.
Of the above particularly preferred compounds of the invention of the formula (IC), chiefly preferred compounds are those wherein R1 is acetamido; R1 is hydrogen or fluoro; R4 and R5 are independently hydrogen, AR-oxymethyl or AR-thiomethyl (wherein AR is phenyl, phenyl(1-4C)alkyl, naphthyl, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole or thiophene), hydroxymethyl, (1-4C)alkoxymethyl or carbamoyl and R7 is cyano, pyrimidin-2-yl, tetrazol-5-yl, 2-cyanoethenyl, 2cyano-2((1-4C)alkyl)ethenyl, or R7 is of the formula R10SO2xe2x80x94 (wherein R10 is hydrogen, (1-4C)alkyl [optionally substituted by hydroxy, (1-4C)alkylS(O)q or (1-4C)alkanoyl wherein q is 0, 1 or 2], phenyl, naphthyl, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, thiophene, benzofuran, benzoimidazole, benzothiophene, benzisothiazole, benzoxazole, benzisoxazole, pyridoimidazole, pyrimidoimidazole, quinoline, quinoxaline, quinazoline, phthalazine, cinnoline or naphthyridine, or R10 is of the formula R11C(O)O(1-6C)alkyl wherein R11 is (1-6C)alkyl), or R7 is of the formula RfC(xe2x95x90O)C(xe2x95x90O)xe2x80x94 wherein Rf is (1-6C)alkoxy; and pharmaceutically-acceptable salts thereof.
Of the above further especially preferred compounds of the invention of the formula (IC), particular especially preferred compounds are those wherein R1 is acetamido; R2 is hydrogen or fluoro; R4 and R5 are hydrogen; and R7 is pyrimidin-2-yl, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl, or R7 is of the formula R10COxe2x80x94 (wherein R10 is hydrogen or (1-4C)alkyl [optionally substituted by hydroxy or (1-4C)alkylS(O)q wherein q is 0, 1 or 2], or R10 is of the formula R11C(O)O(1-6C)alkyl wherein R11 is (1-6C)alkyl), or R7 is of the formula RfC(xe2x95x90O)C(xe2x95x90O)xe2x80x94 wherein Rf is (1-6C)alkoxy; and pharmaceutically-acceptable salts thereof.
Of the above chiefly preferred compounds of the invention of the formula (IC), particular chiefly preferred compounds are those wherein R1 is acetamido; R2 is hydrogen or fluoro; R4 and R5 are hydrogen; and R7 is pyrimidin-2-yl, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl, or R7 is of the formula R10SO2xe2x80x94 (wherein R10 is hydrogen or (1-4C)alkyl [optionally substituted by hydroxy or (1-4C)alkylS(O)q wherein q is 0, 1 or 2],;or R10 is of the formula R11C(O)O(1-6C)alkyl wherein R11 is (1-6C)alkyl), or R7 is of the formula RfC(xe2x95x90O)C(xe2x95x90O)xe2x80x94 wherein Rf is (1-6C)alkoxy; and pharmaceutically-acceptable salts thereof.
Of the above particular especially preferred compounds of the invention of the formula (IC), the most preferred are those wherein R1 is acetamido; R2 is hydrogen or fluoro; R4 and R5 are hydrogen; and R7 is pyrimidin-2-yl, or R7 is of the formula R10COxe2x80x94 (wherein R10 is hydrogen or (1-4C)alkyl [optionally substituted by hydroxy or (1-4C)alkylS(O)q wherein q is 0, 1 or 2], or R10 is of the formula R11C(O)O(1-6C)alkyl wherein R11 is (1-6C)alkyl), or R7 is of the formula RfC(xe2x95x90O)C(xe2x95x90O)xe2x80x94 wherein Rf is (1-6C)alkoxy; and pharmaceutically-acceptable salts thereof.
Of the above particular chiefly preferred compounds of the invention of the formula (IC), the most preferred are those wherein R1 is acetamido; R2 is hydrogen or fluoro; R4 and R5 are hydrogen; and R7 is pyrimidin-2-yl, or R7 is of the formula R10SO2xe2x80x94 (wherein R10 is hydrogen or (1-4C)alkyl [optionally substituted by hydroxy or (1-4C)alkylS(O)q wherein q is 0, 1 or 2], or R10 is of the formula R11(O)O(1-6C)alkyl wherein R11 is (1-6C)alkyl), or R7 of the formula RfC(xe2x95x90O)C(xe2x95x90O)xe2x80x94 wherein Rf is (1-6C)alkoxy; and pharmaceutically-acceptable salts thereof.
Particular compounds of the present invention are:
N-((5S)-3-(4-(1-tertbutoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-(5S)-3-(4-(1,2,5,6-tetrahydropyrid-4yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-(5S)-3-(4-(1-methoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(4-(1-methylsulfonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(4-(1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(4-(1-dimethylaminoacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(4-(2,3-dihydropyran-4-yl)-phenyl)-2oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(4-(2,3-dihydrothiapyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(4-(2,3-dihydrooxothiapyran-4yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(4-(2,3-dihydrodioxothiapyrany-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(3-fluoro-4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(3-fluoro-4-(1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxo-oxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(3-fluoro-4-(1-tertbutoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxo-5-oxazolidinylmethyl)acetamide;
N-((5S)-3-(3-fluoro-4-(1-methoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(3-fluoro-4-(1-methylsulfonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(3-fluoro-4-(1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(3-fluoro-4-(1-dimethylaminoacetyl-1,2,5,6-tetrahydropyrid-4yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(3-fluoro-4-(2,3-dihydropyran-4-yl)-phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(3-fluoro-4-(2,3-dihydrothiapyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(3-fluoro-4-(2,3-dihydrooxothiapyran-4yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(4-(2,3-dihydrodioxothiapyrany-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(4-(1-(pyrimidin-2-yl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(4-(1-cyano-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(3-fluoro-4-(1-(acetoxyacetyl-1,2,5,6-tetrahydropyrid-4yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
5R-hydroxymethyl-3-(3-fluoro4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl) phenyl)oxazolidin-2-one;
N-((5S)-3-(3-fluoro-4-(1-(pyrimidin-2-yl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(3-fluoro-4(1-cyano-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N(5S)-3-(3-fluoro-4-(1-methoxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(3-fluoro-4-(1-methoxalyl-1,2,5,6-tetrahydropyrid-4yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(3-fluoro-4-(1-(N-methylcarbamoyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)2-oxooxazolidin-5-ylmethyl)acetamide;
and pharmaceutically-acceptable salts thereof.
Other particular compounds of the present invention are
N-((5S)3-(4-(1-(2-cyano-2-methylethenyl)1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxo-oxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(4-(1-(hydroxymethylsulfonyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxo-oxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(4-(1-(methylsulfonylaminomethylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxo-oxazolidin-5-ylmethyl)acetamide;
and pharmaceutically-acceptable salts thereof.
Particularly preferred compounds of the present invention are:
N-((5S)-3-(4-(1-methylsulfonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxo-oxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(4-(1-acetyloxymethylcarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(4-(1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N(5S)-3-(3-fluoro-4-(acetyloxymethylcarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(3-fluoro-4-(1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N((5S)-3-(4-(2,3dihydro-6H-pyran-4-yl)phenyl)-2oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(3-fluoro-4-(2,3-dihydro-6H -pyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N(5S)-3-(3-fluoro-4-(1-{pyrimid-2-yl}-1,2,5,6-tetrahydropyrid-4yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(3-fluoro-4-(1-methylsulfonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(4-{pyrimid-2-yl}-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(3-fluoro-4-(1-acetoacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(4-(-(naphth-2-ylsulfonyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(4-(1-(naphth-2-oxyacetyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-(5S)-3-(4-(1-methylthioacetyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
and pharmaceutically-acceptable salts thereof.
Especially preferred compounds of the invention are:
N-((5S)-3-(4-(1-methylsulfonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxo-xazolidin-5-ylmethyl)acetamide:
N-((5S)-3-(4-(1-acetyloxymethylcarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(4-(1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(3-fluoro-4-(1-acetyloxymethylcarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N(5S)-3-(3-fluoro-4-(1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(4(2,3-dihydro-6H-pyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(3-fluoro-4-(2,3-dihydro-6H-pyran-4-yl)phenyl2-oxooxazolidin-5-ylmethyl)acetamide;
and pharmaceutically-acceptable salts thereof
Other especially preferred compounds of the invention are:
N-((5S)-3-(3-fluoro-4-(-1-{pyrimid-2-yl}-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(3-fluoro-4-(1-methylsulfonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(4-(1-{pyrimid-2-yl}-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N-((5S)-3-(3-fluoro-4-(1-acetoacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N(5S)-3-(4-(1-(naphth-2-ylsulfonyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N(5S)-3-(4-(1-(naphth-2-oxyacetyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
N(5S)-3-(4-(1-(methylthioacetyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;
and pharmaceutically-acceptable salts thereof.
In a further aspect the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically-acceptable salt thereof. The compounds of formula (I) may be prepared by deprotecting a compound of formula (II): 
wherein R2, R3 and R6 are as hereinabove defined, R18 is R4 or protected R4, R19 is R5 or protected R5, R20 is R1 or protected R1,  greater than A1xe2x80x94B1xe2x80x94 is  greater than Axe2x80x94Bxe2x80x94 or protected  greater than Axe2x80x94Bxe2x80x94 and D1 is D in which functional group are optionally protected; and thereafter, if necessary, forming a pharmaceutically-acceptable salt.
Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
Specific examples of protecting groups are given below for the sake of convenience, in which xe2x80x9clowerxe2x80x9d signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope of the invention.
A carboxy protecting group may be the residue of an ester-forming aliphatic or araliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms).
Examples of carboxy protecting groups include straight or branched chain (1-12C)alkyl groups (eg isopropyl, t-butyl); lower alkoxy lower alkyl groups (eg methoxymethyl, ethoxymethyl, isobutoxymethyl; lower aliphatic acyloxy lower alkyl groups, (eg acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (eg 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); aryl lower alkyl groups (eg p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (eg trimethylsilyl and t-butyldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups (eg trimethylsilylethyl); and (2-6C)alkenyl groups (eg alkyl and vinylethyl).
Methods particularly appropriate for the removal of carboxyl protecting groups include for example acid-, metal- or enzymically-catalysed hydrolysis.
Examples of hydroxy protecting groups include lower alkenyl groups (eg alkyl); lower alkanoyl groups (eg acetyl); lower alkoxycarbonyl groups (eg t-butoxycarbonyl); lower alkenyloxycarbonyl groups (eg alkyloxycarbonyl); aryl lower alkoxycarbonyl groups (eg benzoyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); tri lower alkyl/arylsilyl groups (eg trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl); aryl lower alkyl groups (eg benzyl)groups; and triaryl lower alkyl groups (eg triphenylmethyl).
Examples of amino protecting groups include formyl, aralkyl groups (eg benzyl and substituted benzyl, eg p-methoxybenzyl, nitrobenzyl and 2,4dimethoxybenzyl, and triphenylmethyl); di-p-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (eg t-butoxycarbonyl); lower alkenyloxycarbonyl (eg alkyloxycarbonyl); aryl lower alkoxycarbonyl groups (eg benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl; trialkylsilyl (eg trimethylsilyl and t-butyldimethylsilyl); alkylidene (eg methylidene); benzylidene and substituted benzylidene groups.
Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, metal- or enzymically-catalysed hydrolysis, for groups such as o-nitrobenzyloxycarbonyl, photolytically and for groups such as silyl groups, fluoride.
Examples of protecting groups for amide groups include aralkoxymethyl (eg. benzyloxymethyl and substituted benzyloxymethyl); alkoxymethyl (eg. methoxymethyl and trimethylsilylethoxymethyl); tri alkyl/arylsilyl (eg. trimethylsilyl, t-butyldimethylsily, t-butyldiphenylsilyl); tri alkyl/arylsilyloxymethyl (eg. t-butyldimethylsilyloxymethyl, t-butyldiphenylsilyloxymethyl); 4-alkoxyphenyl (eg. 4-methoxyphenyl); 2,4-di(alkoxy)phenyl (eg. 2,4-dimethoxyphenyl); 4-alkoxybenzyl (eg. 4-methoxybenzyl); 2,4-di(alkoxy)benzyl (eg. 2,4-di(methoxy)benzyl); and alk-1-enyl (eg. allyl, but-1-enyl and substituted vinyl eg. 2-phenylvinyl).
Aralkoxymethyl, groups may be introduced onto the amide group by reacting the latter group with the appropriate aralkoxymethyl chloride, and removed by catalytic hydrogenation. Alkoxymethyl, tri alkyl/arylsilyl and tri alkyl/silyl groups may be introduced by reacting the amide with the appropriate chloride and removing with acid, or in the case of the silyl containing groups fluoride ions. The alkoxyphenyl and alkoxybenzyl groups are conveniently introduced by arylation or alkylation with an appropriate halide and removed by oxidation with ceric ammonium nitrate. Finally alk-1-enyl groups may be introduced by reacting the amide with the appropriate aldehyde and removed with acid.
For further examples of protecting groups see one of the many general texts on the subject, for example, xe2x80x98Protective Groups in Organic Synthesisxe2x80x99 by Theodora Green (publisher: John Wiley and Sons).
In another aspect of the present invention the compounds of the formulae (I) and (II) and pharmaceutically-acceptable salts thereof can be prepared:
(a) by modifying a substituent in or introducing a substituent into another compound of. formula (I) or (II);
(b) when R1 or R20 is of the formula xe2x80x94NHS(O)n(1-4C)alkyl, wherein n is 1or 2, by oxidising a compound of the formula (I) or (II) wherein n is 0 or, when n is 2 by oxidising a compound of the formula (I) or (II) wherein n is 1;
(c) when R1 or R20 is of the formula xe2x80x94NHC(xe2x95x90O)Rb or NHS(O)n(1-4C)alkyl, introducing the group xe2x80x94C(xe2x95x90O)Rb or xe2x80x94S(O)n(1-4C)alkyl into a compound of the formula (III); 
(d) when R1 or R20 is hydroxy, by reacting a compound of the formula (V) with a compound of formula (VI): 
(e) when  greater than A1xe2x80x94B1xe2x80x94 is  greater than Cxe2x95x90CRa1xe2x80x94, by reacting a compound of the formula (VII) with a compound of the formula (VIII): 
(f) when  greater than A1xe2x80x94B1xe2x80x94 is  greater than CHCH(Ra1)xe2x80x94, by catalytic hydrogenation of a compound of the formula (I) or (II) wherein  greater than A1xe2x80x94B1xe2x80x94 is  greater than Cxe2x95x90CRa1xe2x80x94;
(g) when  greater than A1xe2x80x94B1xe2x80x94 is  greater than Cxe2x95x90CRa1xe2x80x94, by elimination of the elements of water, or HOCOR23, or HOSO2R24 from a compound of the formula (IX) (ie. when R25 is xe2x80x94H, xe2x80x94COR23 or xe2x80x94SO2R24). 
(h) when D is NR7 and R7 is R10COxe2x80x94 or R10S(O)nxe2x80x94, wherein n is 2, by reaction of a compound of formula (X) with a compound of the formula (XI) or (II), wherein n is 2: 
(i) when R1 or R20 is azido, by reacting a compound of the formula (XIII) with a source of azide: 
(j) when R1 or R20 is amino, by reducing a compound of the formula (I) or (II) wherein R1 or R20 is azido;
(k) when R1 or R20 is chloro, fluoro, (1-4C)alkanesulfonyloxy, or (1-4C)alkylaminocarbonyloxy, or R20 is of the formula xe2x80x94N(CO2R27)CO(1-4C)alkyl; from a compound of the formula (I) and (II) wherein R1 or R20 is hydroxy; or
(l) when R1 or R20 is chloro, (1-4C)alkylthio or (1-4C)alkoxy, from a compound of the formula (III);
wherein R2, R3, R6 and R20 are as hereinabove defined; Ra1 is Ra or protected Ra; R21 is (1-6C)alkyl or benzyl; R22 is of the formula (1-4C)alkyl or xe2x80x94S(O)n(1-4C)alkyl; R23 is (1-4C)alkyl; R24 is an optionally substituted phenyl group; R25 is hydrogen, xe2x80x94COR23 or xe2x80x94SO2R24; R26 is mesyloxy or tosyloxy; R27 is (1-4C)alkyl or benzyl; n is 0, 1 or 2 unless otherwise stated above. L1 is an iodo or triflate leaving group; L2 is a leaving group, such as, for example, hydroxy or chloro; and Y is a trialkyltin residue or a boronate acid or ester residue;
and thereafter if necessary:
i) removing any protecting groups;
ii) forming a pharmaceutically-acceptable salt.
Methods for converting substituents into other substituents are known in the art For example an alkylthio group may be oxidised to an alkylsulfinyl or alkysulfonyl group, a cyano group reduced to an amino group, a nitro group reduced to an amino group, a hydroxy group alkylated to a methoxy group, a hydroxy group thiomethylated to an arylthiomethyl or a heteroarylthiomethyl group (see, for example, Tet.Lett., 585, 1972), a carbonyl group converted to a thiocarbonyl group (eg. using Lawsson""s reagent) or a bromo group converted to an alkylthio group.
Compounds of the formula (I) or (II) wherein R1 or R20 is xe2x80x94NHS(O)n(1-4C)alkyl can be prepared by oxidising a compound of the formula (I) or (II) with standard reagents known in the art for the oxidation of a thio group to a sulfinyl or sulfonyl group. For example, a thio group may be oxidised to a sulfinyl group with a peracid such as m-chloroperoxybenzoic acid and oxidising agents such as potassium permanganate can be used to convert a thio group to a sulfonyl group. Compounds of the formula (I) or (II) wherein R1 or R20 is xe2x80x94NHS(1-4C)alkyl can be prepared by reacting compounds of the formula (III) with a reagent such as (1-4C)alkylSCl.
When Rb is (1-4C)alkyl, the group xe2x80x94C(xe2x95x90O)(1-4C)alkyl may be introduced into a compound of the formula (III) by standard acetylation procedures. For example, the amino group may be acetylated to give an acetamido group using the Schotten-Baumann procedure i.e. reacting the compound of the formula (I) or (II) wherein R1 or R20 is amino with acetic anhydride in aqueous sodium hydroxide and THF in a temperature range of 0xc2x0 C. to ambient temperature. Preferably the acylation is carried out in situ following the catalytic hydrogenation of a compound of the formula (I) or (II) wherein R1 or R20 is azido, by performing the hydrogenation in the presence of acetic anhydride.
When Rb is hydrogen, the xe2x80x94CHO group may be introduced into the compound of the formula (III) by reacting the latter compound with formic acetic anhydride, in an inert organic solvent such as THF, in a temperature range of 0xc2x0 C. to ambient temperature, or by reacting it with ethyl formate in an inert organic solvent in the temperature range of 50-100xc2x0 C.
When Rb is (1-4C)alkoxy, the xe2x80x94COO(1-4C)alkyl group may be introduced into the compound of the formula (III) by reacting the latter compound with (1-4C)alkyl chloroformate, in the presence of an organic base such as triethylamine, in an organic solvent such as dichloromethane and in a temperature range of 0xc2x0 C. to ambient temperature.
When Rb is amino, the xe2x80x94CONH2 group may be introduced into the compound of the formula (III) by reacting the latter compound either with potassium cyanate in aqueous acid (eg hydrochloric acid) in a temperature range of ambient temperature to 40xc2x0 C. or with phenyl carbamate in glyme at reflux.
When Rb is chloromethyl, dichloromethyl, cyanomethyl or methoxymethyl, the xe2x80x94C(xe2x95x90O)Rb group may be introduced into the compound of the formula (III) by reacting the latter compound with the appropriate acid chloride under standard conditions. The acid chloride may be prepared from the appropriate acid. When Rb is acetylmethyl, the xe2x80x94C(xe2x95x90O)Rb group may be introduced into the amino compound by reacting the latter compound with diketene, in an inert organic solvent such as THF, in a temperature range of 0xc2x0 C. to ambient temperature.
Alternatively, the compound of the formula (III) may be reacted with the appropriate acid anhydride, in dichloromethane or THF, in the presence of an organic base such as triethylamine and in a temperature range of 0xc2x0 C. to ambient temperature, or the amino compound may be reacted with the appropriate acid in the presence of 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride and an organic base such as triethylamine, in an organic solvent such as dichloromethane, in a temperature range of 0xc2x0 C. to ambient temperature.
When Rb is methylamino, the xe2x80x94CONHMe group may be introduced into the compound of the formula (III) by reacting the latter compound with methyl isocyanate in an organic solvent such as THF or acetonitrile, in a temperature range of 0xc2x0 C. to ambient temperature.
When Rb is dimethylamino, the xe2x80x94CONMe2 group may be introduced into the compound by of the formula (III) by reacting the latter compound with dimethylcarbamoyl chloride and triethylamine in an organic solvent such as THF or acetonitrile, in a temperature range of 0xc2x0 C. to ambient temperature.
Standard reaction conditions for the conversion of a compound of the formula (III) to a compound of the formula (I) or (II) wherein R1 or R20 is sulfonamido are known in the art. For example, a compound of the formula (III) could be converted to a compound of the formula (I) or (II) wherein R1 or R20 is (1-4C)alkylSO2NHxe2x80x94 by reacting the former compound with a sulfonyl chloride, for example, mesyl chloride, in a mild base such as pyridine or triethylamine.
Alternatively compounds of the formula (I) or (II) wherein R1 or R20 is (1-4C)alkylSO2NHxe2x80x94 or (1-4C)alkylSONHxe2x80x94 may be prepared by reacting a compound of the formula (III) with a compound of the formula (IV): 
The compound of the formula (IV) may be prepared by oxidising a compound of the formula (IVA): 
with standard oxidising agents known for the conversion of a thio group to a sulfinyl or sulfonyl group.
Compounds of the formula (IVA) can be prepared by reacting phthalimide with an alkylthiochloride ((1-4)alkylSCl).
A compound of the formula (III) may be prepared as described in process (j).
Compounds of the formulae (V) and (VI) are conveniently reacted together in the presence of a strong base such as butyl lithium, lithium hexamethyldisilazide, sodium hydride, or lithium diisopropylamide. The reaction is conveniently carried out in an inert solvent such as tetrahydrofuran (THF), dimethylformamide (DMF), N,N1-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone in a temperature range of xe2x88x9278xc2x0 C. to xe2x88x9250xc2x0 C. for the deprotonation and cyclisation. Suitable values for R21 include ethyl, butyl and benzyl and suitable values for R22 include ethyl and n-propyl, preferably n-propyl.
A compound of the formula (V) is conveniently prepared by reacting a chloroformate of the formula (ClCOOR21) with a compound of the formula (VA): 
wherein R3-R5 and  greater than A1xe2x80x94B1xe2x80x94 are as hereinabove defined. The reaction is conveniently carried out in the presence of an inorganic or organic base such as sodium bicarbonate or an amine base such as dimethylaniline, the former in a solvent such as acetone/water and the latter in an organic solvent such as THF, toluene, DMF or acetonitrile.
A compound of the formula (VA) wherein  greater than A1xe2x80x94B1xe2x80x94 is  greater than Cxe2x95x90CHxe2x80x94, may be prepared by reacting a compound of the formula (VIII) with a compound of the formula (VB). 
The reaction between compounds of the formulae (VIII) and (VB) wherein L3 is bromo or iodo may be is carried out by treating (VB) with an organolithium species such as 1-butyl methyl in an inert solvent such as THF at a low temperature, such as xe2x88x9278xc2x0 C., followed by the addition of an anhydrous zinc halide such as zinc chloride, in a temperature range of 0xc2x0 C. to ambient temperature, to generate the organozinc chloride (VB), wherein L1 is ZnCl. Treatment of the organozinc chloride in situ with a compound of the formula (VIII) followed by a suitable palladium [0] catalyst such as Pd(PPh3)4, in the temperature range of 0xc2x0 C. to ambient temperature, results in the cross-coupled product (VA) after brief treatment with dilute acid to hydrolyse the xe2x80x98stabasexe2x80x99 protected amine.
A compound of the formula (VB) may be prepared by treatment of p-iodo or p-bromoaniline with the xe2x80x98stabasexe2x80x99 reagent (1,2-bis(chlorodimethylsilyl)ethane) in the presence of an organic base such as triethylamine.
The reaction between compounds of the formulae (VII) and (VIII), wherein Y is trialkyltin and L1 is triflate is conveniently carried out in the presence of a palladium (0) catalyst such as Pd(PPh3)4 or Pd(dba)3 in a temperature range of 0-115xc2x0 C. Preferably the trialkyltin group is trimethyltin. A suitable value for L1 is iodo or trifluoromethylsulfonyloxy.
When Y is a boronate acid or ester, the reaction may be carried out under conditions known for the Suzuki reaction i.e. in the presence of a palladium (0) catalyst such as Pd(PPh)3)4 or Pd(dba)3, in a water-miscible organic solvent such as dimethylformamide or 1,2dimethoxyethane and in the presence of a mild base such as sodium acetate or sodium bicarbonate which is added in water. The reaction is then heated to 80xc2x0 C. Alternatively, silver oxide may be used in place of the base, in which case the reaction may be carried out at a lower temperature. When Y is a boronate ester, preferably L1 is iodo. Suitable boronate esters include lower alkyl and cyclic boronate esters.
A compound of the formula (VII) wherein Y is trimethylstannyl may be prepared by methods known in the art (for example by using methods similar to those described in Patent Application No. WO 9413649 from a compound of the formula (VII) wherein Y is iodo or bromo). Alternatively compounds of the formula (VII) wherein Y is a cyclic boronate ester as in (VIIA): 
may be prepared from a compound of the formula (VII) wherein Y is iodo or bromo, by sequential treatment with a suitable Pd catalyst such as PdCl2(dppf), potassium acetate and the pinacol ester of diboron in a polar solvent such as DMSO (for example see J. Org. Chem., 1995, 60, 7508-7510).
A compound of the formula (VII), wherein Y is iodo may be prepared by reacting a compound of the formula (VIIB) with iodine monochloride in the presence of trifluoroacetic acid or with iodine and silver triflate: 
When Y is bromo, a compound of the formula (VII) may be prepared by brominating a compound of the formula (VIIB) using standard bromination methods. For example, by reacting a compound of the formula (VIIB) with N-bromosuccinimide or bromine.
A compound of the formula (VIIB) may be prepared by forming the oxazolidinone ring from the amino group of a compound of the formula (VIIC) using a similar method to that described for the preparation of a compound of the formula (I) or (II) from a compound of the formula (VA): 
The resulting compound of the formula (VIIB) in which R20 is hydroxy may be converted to other compounds of the formula (VIIB) using similar methods to those described for the formation of a compound of the formula (I) or (II) from a compound of the formula (I) or (II) wherein R1 or R20 is hydroxy, via a compound of the formula (III).
A compound of the formula (VIII) wherein D1 is R10CONxe2x80x94, S or O and L1 is triflate may be prepared by treating a compound of the formula (VIIIA) with lithium diisopropylamide in an inert solvent such as THF, at a low temperature. for example xe2x88x9278xc2x0 C., followed by N-phenyl triflamide (for example, see methods described in Synthesis, 993-95 (1991)). 
Alternatively, a compound of the formula (VIII) wherein L1 is iodo may be prepared by treating a hydrazone of a compound of formula (VIIIA) with iodine in the presence of triethylamine (for example see methods detailed in Tet. Letts., 24, 1605-1608 (1983)).
Compounds of the formula (VIII) wherein D1 is R14CH(R13)(CH2)mxe2x80x94N less than , aryl-N less than  or heteroaryl(mono or bicyclic)-N can be prepared by elaboration of the piperidone ring from the appropiate aryl- or heteroarylamine, by reaction with ethyl acrylate to give the corresponding diethylarylimino-bb-dipropionate, which can then be cyclised under Diekmann conditions to the give corresponding piperidone b-ketoester, followed by decarboxylation with heating in acid (see methods described in J.Chem.Soc., 5110-5118 (1962)).
Alternatively, a compound of the formula (VIII) wherein D1 is heteroaryl-N less than  may be prepared by reacting an appropiately substituted heterocycle containing a leaving group such as chloro, bromo or iodo with the appropriate 4-piperidone at an elevated temperature, in an inert solvent and optionally with an acid trapping agent.
Suitable catalysts for the catalytic hydrogenation of a compound of the formula (I) or (II) wherein  greater than A1xe2x80x94B1xe2x80x94 is  greater than Cxe2x95x90C(Ra1)xe2x80x94 include Raney nickel, platinum metal or its oxide, rhodium, zinc oxide, palladium-on-charcoal and Wilkinson""s catalyst (RhCl(Ph3P)3. Catalyic hydrogenation is conveniently carried out in the temperature range 0xc2x0 C. to 150xc2x0 C., but preferably at ambient temperature and pressure, unless Wilkinson""s catalytic is used in which case a temperature of approximately 50xc2x0 C. and pressure of approximately 50 atmospheres are preferable.
A compound of the formula (IX) may be prepared by reacting an intermediate of the formula (VB) with magnesium to form a Grignard reagent, or alternatively with n-butyl lithium to form a lithiated species (as above), and then reacting the Grignard reagent or lithiated species with a compound of formula (VIIIA). The product (VA), wherein  greater than A1xe2x80x94B1xe2x80x94 is of the formula  greater than C(OH)CH(Ra)xe2x80x94 may then be elaborated as previously detailed for the compound of the formula (V), but with optional protection of the hydroxyl group.
The dehydration of a compound of the formula (IX) to give a compound of formula (I) or (II) wherein  greater than A1xe2x80x94B1xe2x80x94 is of the formula  greater than Cxe2x95x90CRa1xe2x80x94 may be carried out using agents such as polyphosphoric acid, trifluoroacetic acid, trifluoroacetic anhydride, p-toluenesulfonic acid, sulfuric acid, thionyl chloride etc., in an inert solvent such as toluene, and at elevated temperatures. Suitable protection of the group R20 may be necessary as appropriate.
A compound of the formula (I) or (II) wherein  greater than A1xe2x80x94B1xe2x80x94 is of the formula  greater than CHCH(Ra1)xe2x80x94 may be prepared from a compound of the formula (I) or (II) wherein  greater than A1xe2x80x94B1xe2x80x94 is  greater than Cxe2x95x90CRa1xe2x80x94, by catalytic hydrogenation, using a suitable catalyst such as palladium-on-carbon in an appropiate inert or acidic solvent such as acetic acid. Where an optically active form of compounds of the formula (VI) is used in previous steps, reduction of the  greater than A1xe2x80x94B1xe2x80x94 double bond will produce diastereoisomers which may be separated. Where a particular diastereoisomer is of choice, a chiral asymmetry-inducing catalyst for the reduction can be used.
The reaction between a compound of the formula (X) and (XI) or (XII) is conveniently carried out under similar conditions to those described for the acetylation or sulfonylation of a compound of the formula (III).
A compound of the formula (I) or (II) wherein R1 or R20 is azido may be prepared, for example, by reacting a compound of the formula (XIII) with sodium azide in an inert solvent such as DMF in a temperature range of ambient to 100xc2x0 C., normally in the region of 75xc2x0 C.-85xc2x0 C. A compound of the formula (XI) may be prepared by converting the hydroxy group in a compound of the formula (I) or (II) wherein R1 or R20 is hydroxy into a tosyloxy or mesyloxy group by standard methods known in the art. For example, by reacting the compound of the formula (I) or (II) with tosyl chloride or mesyl chloride in the presence of a mild base such as triethylamine, or pyridine.
Suitable reducing agents for reducing azido to amino in a compound of the formula (I) or (II) include triethylamine/hydrogen sulfide, triphenylphosphine or phosphite ester, or hydrogen in the presence of a catalyst. More specifically the reduction of the azido group may be carried out by heating it in an aprotic solvent, such as 1,2-dimethoxyethane, in the presence of P(OMe)3 and subsequently heating in 6N aqueous hydrochloric acid, or reacting it with hydrogen in the presence of palladium on carbon in a solvent such as DMF or ethyl acetate. For further details on the reduction of azides to amines see U.S. Pat. No. 4,705,799. The azido compound may be reduced and converted to a compound of the formula (I) or (II), wherein R1 or R10 is acetamido, in situ using acetic anhydride in DMF.
A compound of the formula (I) or (II) wherein R1 or R20 is fluoro may be prepared by reacting a compound of the formula (I) or (II) wherein R1 or R20 is hydroxy (hydroxy compound) with a fluorinating agent such as diethylaminosulfur trifluoride in an organic solvent such as dichloromethane in the temperature range of 0xc2x0 C. to ambient temperature.
When R1 or R20 is chloro, the compound of the formula (I) or (II) may be formed by reacting the hydroxy compound with a chlorinating agent. For example, by reacting the hydroxy compound with thionyl chloride, in a temperature range of ambient temperature to reflux, optionally in a chlorinated solvent such as dichloromethane or by reacting the hydroxy compound with carbon tetrachloride/triphenyl phosphine in dichloromethane, in a temperature range of 0xc2x0 C. to ambient temperature.
The (1-4C)alkanesulfonyloxy compound may be prepared by reacting the hydroxy compound with (1-4C)alkanesulfonyl chloride in the presence of a mild base such as triethylamine or pyridine.
The (1-4C)alkylaminocarbonyloxy compound may be prepared by reacting the hydroxy compound with (1-4C)alkyl cyanate in an organic solvent such as THF or acetonitrile, in the presence of triethylamine, in a temperature range of 0xc2x0 C. to 50xc2x0 C.
A compound of the formula (II) wherein R20 is of the formula xe2x80x94N(CO2R27)CO(1-4C)alkyl is conveniently prepared by reacting a compound of the formula (I) and (II) wherein R1 or R20 is hydroxy with an amide of the formula HN(CO2R27)CO(1-4C)alkyl under Mitsunobu conditions. For example, in the presence of tri-n-butylphosphine and 1,1xe2x80x2-(azodicarbonyl)dipiperidine in an organic solvent such as THF, and in the temperature range 0xc2x0 C.-60xc2x0 C., but preferably at ambient temperature. Details of analogous Mitsunobu reactions are contained in Tsunoda et al, Tet. Letts., 34, 1639, (1993). Amides of the formula HN(CO2R27)CO(1-4C)alkyl may be prepared by standard procedures of organic chemistry which are within the ordinary skill of an organic chemist.
A compound of the formula (I) or (II) wherein R1 or R20 is chloro may also be prepared from a compound of the formula (XII), by reacting the latter compound with lithium chloride and crown ether, in a suitable organic solvent such as THF, in a temperature range of ambient temperature to reflux. A compound of the formula (I) or (II) wherein R1 or R20 is (1-4C)alkylthio or (1-4C)alkoxy may be prepared by reacting the compound of the formula (XI) with sodium thio(1-4C)alkoxide or sodium (1-4C)alkoxide respectively, in an alcohol or THF, in a temperature range of 0xc2x0 C. to reflux.
It is also possible to convert one R7 group into another R7 group as a final step in the preparation of a compound of the formula (I) or (II) (see the specific examples).
When an optically active form of a compound of the formula (I) is required, it may be obtained by carrying out one of the above procedures using an optically active starting material, or by resolution of a racemic form of the compound or intermediate using a standard procedure.
Similarly, when a pure regioisomer of a compound of the formula (I) is required, it may be obtained by carrying out one of the above procedures using a pure regioisomer as a starting material, or by resolution of a mixture of the regioisomers or intermediates using a standard procedure.
According to a further feature of the invention there is provided a compound of the formula (I), or a pharmaceutically-acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy.
According to a further feature of the present invention there is provided a method for producing an antibacterial effect in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically-acceptable salt thereof.
The invention also provides a compound of the formula (I), or a pharmaceutically-acceptable salt thereof, for use as a medicament; and the use of a compound of the formula (I) of the present invention, or a pharmaceutically-acceptable salt thereof, in the manufacture of a novel medicament for use in the production of an antibacterial effect in a warm blooded animal, such as man.
In order to use a compound of the formula (I) or a pharmaceutically-acceptable salt thereof for the therapeutic treatment of mammals including humans, in particular in treating infection, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically-acceptable salt thereof and a pharmaceutically-acceptable diluent or carrier.
The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain or be co-administered with one or more known drugs selected from other clinically useful antibacterial agents (for example xcex2-lactams or aminoglycosides). These may include penicillins, for example oxacillin or flucloxacillin and carbapenems, for example meropenem or imipenem, to broaden the therapeutic effectiveness against methicillin-resistant staphylococci. Compounds of this invention may also contain or be co-administered with bactericidal/permeability-increasing protein product (BPI) or efflux pump inhibitors to improve activity against gram negative bacteria and bacteria resistant to antimicrobial agents.
A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 100 mg and 1 g of the compound of this invention.
In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
Each patient may receive, for example, a daily intravenous. subcutaneous or intramuscular dose of 5 mgkgxe2x88x921 to 20 mgkgxe2x88x921 of the compound of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
Antibacterial Activity
The pharmaceutically-acceptable compounds of the present invention are useful antibacterial agents having a good spectrum of activity in vitro against standard Gram-positive organisms, which are used to screen for activity against pathogenic bacteria. Notably, the pharmaceutically-acceptable compounds of the present invention show activity against enterococci, pneumococci and methicillin resistant strains of S. aureus and coagulase negative staphylococci. The antibacterial spectrum and potency of a particular compound may be determined in a standard test system.
The antibacterial properties of the compounds of the invention may also be demonstrated in-vivo in conventional tests. No overt toxicity or other untoward effects are observed when compounds of the formula I are so tested.
The following results were obtained on a standard in-vitro test system. The activity is described in terms of the minimum inhibitory concentration (MIC) determined by the agar-dilution technique with an inoculum size of 104 CFU/spot.
Staphylococci were tested on agar, using an inoculum of 104 CFU/spot and an incubation temperature of 37xc2x0 C. for 24 hoursxe2x80x94standard test conditions for the expression of methicillin resistance.
Streptococci and enterococci were tested on agar supplemented with 5% defibrinated horse blood, an inoculum of 104 CFU/spot and an incubation temperature of 37xc2x0 C. in an atmosphere of 5% carbon dioxide for 48 hoursxe2x80x94blood is required for the growth of some of the test organisms.
Novb. Res=Novobiocin resistant
MRQS=methicillin resistant quinolone sensitive
MRQR=methicillin resistant quinolone resistant
MR=methicillin resistant
MS=methicillin sensitive